13,835 research outputs found
Trends in Kaposi's sarcoma-associated Herpesvirus antibodies prior to the development of HIV-associated Kaposi's sarcoma: a nested case-control study
HIV-associated Kaposi's sarcoma (KS) is a public health challenge in sub-Saharan Africa since both the causative agent, Kaposi's sarcoma associated-herpesvirus (KSHV), and the major risk factor, HIV, are prevalent. In a nested case-control study within a long-standing clinical cohort in rural Uganda, we used stored sera to examine the evolution of antibody titres against the KSHV antigens K8.1 and latency-associated nuclear antigen (LANA) among 30 HIV-infected subjects who subsequently developed HIV-related KS (cases) and among 108 matched HIV/KSHV coinfected controls who did not develop KS. Throughout the 6 years prior to diagnosis, antibody titres to K8.1 and LANA were significantly higher among cases than controls (p < 0.0001), and titres increased prior to diagnosis in the cases. K8.1 titres differed more between KS cases and controls, compared to LANA titres. These differences in titre between cases and controls suggest a role for lytic viral replication in the pathogenesis of HIV-related KS in this setting
Nonequilibrium brittle fracture propagation: Steady state, oscillations and intermittency
A minimal model is constructed for two-dimensional fracture propagation. The
heterogeneous process zone is presumed to suppress stress relaxation rate,
leading to non-quasistatic behavior. Using the Yoffe solution, I construct and
solve a dynamical equation for the tip stress. I discuss a generic tip velocity
response to local stress and find that noise-free propagation is either at
steady state or oscillatory, depending only on one material parameter. Noise
gives rise to intermittency and quasi-periodicity. The theory explains the
velocity oscillations and the complicated behavior seen in polymeric and
amorphous brittle materials. I suggest experimental verifications and new
connections between velocity measurements and material properties.Comment: To appear in Phys. Rev. Lett., 6 pages, self-contained TeX file, 3
postscript figures upon request from author at [email protected] or
[email protected], http://cnls-www.lanl.gov/homepages/rafi/rafindex.htm
Cephalosporin-3’-diazeniumdiolate NO-donor prodrug PYRRO-C3D enhances azithromycin susceptibility of non-typeable Haemophilus influenzae biofilms
The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.Objectives: PYRRO-C3D is a cephalosporin-3-diazeniumdiolate nitric oxide (NO)-donor prodrug designed to selectively deliver NO to bacterial infection sites. The objective of this study was to assess the activity of PYRRO-C3D against non-typeable Haemophilus influenzae (NTHi) biofilms and examine the role of NO in reducing biofilm-associated antibiotic tolerance.
Methods: The activity of PYRRO-C3D on in vitro NTHi biofilms was assessed through CFU enumeration and confocal microscopy. NO release measurements were performed using an ISO-NO probe. NTHi biofilms grown on primary ciliated respiratory epithelia at an air-liquid interface were used to investigate the effects of PYRRO-C3D in the presence of host tissue. Label-free LC/MS proteomic analyses were performed to identify differentially expressed proteins following NO treatment.
Results: PYRRO-C3D specifically released NO in the presence of NTHi, while no evidence of spontaneous NO release was observed when the compound was exposed to primary epithelial cells. NTHi lacking β-lactamase activity failed to trigger NO release. Treatment significantly increased the susceptibility of in vitro NTHi biofilms to azithromycin, causing a log-fold reduction in viability (p<0.05) relative to azithromycin alone. The response was more pronounced for biofilms grown on primary respiratory epithelia, where a 2-log reduction was observed (p<0.01). Label-free proteomics showed that NO increased expression of sixteen proteins involved in metabolic and transcriptional/translational functions.
Conclusions: NO release from PYRRO-C3D enhances the efficacy of azithromycin against NTHi biofilms, putatively via modulation of NTHi metabolic activity. Adjunctive therapy with NO mediated through PYRRO-C3D represents a promising approach for reducing biofilm associated antibiotic tolerance
A Dynamic Programming Approach to Adaptive Fractionation
We conduct a theoretical study of various solution methods for the adaptive
fractionation problem. The two messages of this paper are: (i) dynamic
programming (DP) is a useful framework for adaptive radiation therapy,
particularly adaptive fractionation, because it allows us to assess how close
to optimal different methods are, and (ii) heuristic methods proposed in this
paper are near-optimal, and therefore, can be used to evaluate the best
possible benefit of using an adaptive fraction size.
The essence of adaptive fractionation is to increase the fraction size when
the tumor and organ-at-risk (OAR) are far apart (a "favorable" anatomy) and to
decrease the fraction size when they are close together. Given that a fixed
prescribed dose must be delivered to the tumor over the course of the
treatment, such an approach results in a lower cumulative dose to the OAR when
compared to that resulting from standard fractionation. We first establish a
benchmark by using the DP algorithm to solve the problem exactly. In this case,
we characterize the structure of an optimal policy, which provides guidance for
our choice of heuristics. We develop two intuitive, numerically near-optimal
heuristic policies, which could be used for more complex, high-dimensional
problems. Furthermore, one of the heuristics requires only a statistic of the
motion probability distribution, making it a reasonable method for use in a
realistic setting. Numerically, we find that the amount of decrease in dose to
the OAR can vary significantly (5 - 85%) depending on the amount of motion in
the anatomy, the number of fractions, and the range of fraction sizes allowed.
In general, the decrease in dose to the OAR is more pronounced when: (i) we
have a high probability of large tumor-OAR distances, (ii) we use many
fractions (as in a hyper-fractionated setting), and (iii) we allow large daily
fraction size deviations.Comment: 17 pages, 4 figures, 1 tabl
Conformational changes of calmodulin upon Ca2+ binding studied with a microfluidic mixer
A microfluidic mixer is applied to study the kinetics of calmodulin conformational changes upon Ca2+ binding. The device facilitates rapid, uniform mixing by decoupling hydrodynamic focusing from diffusive mixing and accesses time scales of tens of microseconds. The mixer is used in conjunction with multiphoton microscopy to examine the fast Ca2+-induced transitions of acrylodan-labeled calmodulin. We find that the kinetic rates of the conformational changes in two homologous globular domains differ by more than an order of magnitude. The characteristic time constants are ≈490 μs for the transitions in the C-terminal domain and ≈20 ms for those in the N-terminal domain of the protein. We discuss possible mechanisms for the two distinct events and the biological role of the stable intermediate, half-saturated calmodulin
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Exploring content and psychometric validity of newly developed assessment tools for itch and skin pain in atopic dermatitis.
BackgroundAtopic dermatitis (AD) is a common skin disorder characterized by chronic inflammation, altered skin barrier function, and inflammatory cell skin infiltration that decreases health-related quality of life (HRQoL). The study objective was to understand the patient perspective of AD burden and determine suitable patient-reported outcome (PRO) measures.MethodsThis mixed methods study involved the collection of qualitative and quantitative information from adults (≥ 18 years old) and adolescents (12 - 17 years old) with clinician-confirmed AD regarding their experiences of AD symptoms and its impact on HRQoL. The first part of the study included three stages: in-person concept elicitation (CE) interviews, a 2-week daily electronic diary (eDiary) study, and in-person cognitive debriefing (CD) interviews. An Itch numeric rating scale (NRS) (v1.0) and a Skin Pain NRS (v1.0) evaluation during CD interviews required participants to think about their 'worst' itch and 'worst' skin pain in the past 24 h. Other PRO measures allowed for psychometric testing. The second part of the study involved telephone-depth interviews (TDIs) and qualitative feedback from participants who had not participated in the CD interviews. Qualitative data were thematically analyzed. Psychometric evaluation of NRS measures was performed using eDiary data.ResultsIn the CE interviews, itch and/or itching and skin pain were the most prevalent symptoms consistently discussed by participants. Both NRS measures demonstrated strong psychometric reliability and were applicable across ages with suitable concurrent validity. During the CD interviews, some participants focused their answers on their 'average' itch/itching in the past 24 h, rather than their 'worst' itch. Some participants answered the Skin Pain NRS thinking about general pain or other types of pain, rather than skin pain specifically. Consequently, modifications to both measures addressed these issues and re-tested as paper-and-pen versions in subsequent TDIs. Itch NRS (v2.0) modifications helped participants focus on their worst itching. Most participants preferred Skin Pain NRS v2.0b, which included skin pain descriptors.ConclusionsItching and skin pain are the most important and relevant AD symptoms. The Itch NRS (v2.0) and Skin Pain NRS (v2.0b) appear to be appropriate endpoints for the assessment of itching and skin pain severity for clinical trials with adults and adolescents with AD
X-ray follow-up observations of the two γ-ray pulsars PSR J1459–6053 and PSR J1614–2230
International audienceAims. We have observed two newly detected γ-ray pulsars, PSR J1459−6053 and PSR J1614−2230, in the X-ray domain withXMM-Newton to try to enlarge the sample of pulsars for which multi-wavelength data exist. We use these data with the aim of understandingthe pulsar emission mechanisms of these pulsars.Methods. We analysed the X-ray spectra to determine whether the emission emanates from the neutron star surface (thermal emission)or from the magnetosphere (non-thermal emission) and compared this to the region in the magnetosphere in which the γ-rayemission is generated. Furthermore, we compared the phase-folded X-ray lightcurves with those in the γ-ray and, where possible,radio domains, to elicit additional information on the emission sites.Results. J1459−6053 shows X-ray spectra that are best fitted with a power law model with a photon index Γ = 2.10+1.24−0.85. The γ-raydata suggest that either the slot gap or the outer gap model may be best to describe the emission from this pulsar. Analysis of theX-ray lightcurve folded on the γ-ray ephemeris shows modulation at the 3.7σ level in the 1.0−4.5 keV domain. Possible alignmentof the main γ-ray and X-ray peaks also supports the interpretation that the emission in the two energy domains emanates from similarregions. The millisecond pulsar J1614−2230 exhibits an X-ray spectrum with a substantial thermal component, where the best-fittingspectral model is either two blackbodies, with kT = 0.15+0.04−0.04 and 0.88+2.54−0.54 keV or a blackbody with similar temperature to the previouscooler component, kT = 0.13+0.04−0.02 keV and a power law component with a photon index Γ = 1.25+2.30−1.75. The cooler blackbodycomponent is likely to originate from the hot surface at the polar cap. Analysis of the X-ray lightcurve folded on the radio ephemerisshows modulation at the 4.0σ level in the 0.4−3.0 keV domain
Moderate-intensity exercise alters markers of alternative activation in circulating monocytes in females: a putative role for PPARγ
Monocytes may be primed towards differentiation into classically activated M1 macrophages or alternatively activated M2 macrophages. M1 macrophages greatly contribute to the inflammation which promotes insulin resistance, whereas M2 macrophages resolve inflammation. We have previously shown that exercise increases M2 marker expression in mixed mononuclear cells, possibly via activation of the nuclear transcription factor PPARγ. However, these effects have not been demonstrated specifically within monocytes. Thus, we aimed to investigate whether moderate-intensity exercise elicited similar effects on monocytic M1/M2 marker expression and PPARγ activity to those reported previously in mononuclear cells, so as to further elucidate the mechanisms by which exercise may alter inflammatory status and, accordingly, prevent insulin resistance
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